Methods and compositions using terfenadine metabolites in combination with leukotriene inhibitors

ABSTRACT

Methods and pharmaceutical compositions employing a terfenadine metabolite and a leukotriene inhibitor for the treatment or prevention of inflammation or allergic disorders, such as asthma, or symptoms thereof. Also included are methods and compositions employing a terfenadine metabolite, a leukotriene inhibitor, and a decongestant for the treatment or prevention of inflammation or allergic disorders, such as asthma, or symptoms thereof.

This is a request for filing a divisional application under 37 CFR§1.53(b), of prior application Ser. No. 09/059,570 now U.S. Pat. No.6,194,431 filed on Apr. 14, 1998.

FIELD OF THE INVENTION

The invention relates to methods of treating asthma, allergicconditions, and inflammation. In another aspect, this invention relatesto the use of antihistamines and leukotriene inhibitors, and tocompositions containing them.

BACKGROUND OF THE INVENTION

Terfenadine is an antagonist of the H-1 histamine receptor protein,which mediates the response antagonized by conventional antihistamines.Terfenadine is well absorbed but is extensively metabolized. SeeOkerholm et al., Biopharmaceutics and Drug Distribution, 2: 185-190(1981). Two main metabolites have been identified and one of themetabolites, fexofenadine, chemically named4-[1-hydroxy-4[4-(hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneaceticacid, is reported to have antihistaminic activity. See Gartiez et al.,Arzneimittel Forschung/Drug-Research; 32: 1185-1190 (1982).

Recently, the FDA has approved the use of fexofenadine as a prescriptionantihistamine (ALLEGRA®) for allergic rhinitis. Fexofenadine is said tohave the beneficial effects of terfenadine while having a reduced riskof cardiotoxicity. See, e.g., U.S. Pat. No. 5,375,683.

It has been suggested that the moderate effectiveness of someH₁-antihistamines are due to their additional activity againstleukotrienes, particularly LTD₄. In one study of guinea pigs, theincrease in airway resistance caused by LTD₄ (leukotriene D₄) wassuppressed by terfenadine. See Akagi et al., Oyo Yakuri, 35: 361-371(1988). Another study was conducted that investigated the development ofdual antagonists of H₁- and LTD₄-receptors. Twenty (20)H₁-antihistamines with diverse chemical structures were tested foractivity against LTD₄-induced contraction in isolated guinea-pig ileumand displacement of [³H] LTD₄ from guinea-pig lung membrane proteins [M.Zhang et al., Tnflamm. res. 46:Supp. I S93-S94 (1997)]. The resultsindicated the drugs were weakly active in inhibiting LTD₄-inducedcontraction of guinea pig ileum. The study further mentioned a possiblemechanism for loratadine and terfenadine, but concluded that themechanism does not appear to warrant great attention for drugdevelopment.

Similarly, F. Baroody et al. report that terfenadine treatment partiallyinhibits the early nasal response to allergen challenge and subsequentreactivity to a challenge with methacholine without affecting the influxof eosinophils into nasal secretions. Treatment tended to decreaselevels of tryptase, prostaglandin D₂ and leukotriene C₄, but thedifferences did not achieve statistical significance relative to theplacebo [F. Baroody et al., Arch. Otolaryngol. Head Neck Surg.,122:309-316 (Mar. 1996)].

Compounds within the class of non-sedating antihistamines have beenknown to cause severe adverse electrophysiologic side-effects whenadministered to a human. These adverse side-effects are associated witha prolonged QT interval and include, but are not limited to, ventricularfibrillation and cardiac arrhythmias, such as ventriculartachyarrhythmias or torsades de pointes. Quercia et al., Hosp. Formul.28: 137, 142 (1993); Knowles, Canadian Journal Hosp. Pharm., 45: 33,37(1992); Craft, British Medical Journal, 292: 660 (1986); Simons et al.,Lancet, 2: 624 (1988); and Unknown, Side Effects of Drugs Annual, 12:142 and 14: 135. More recently, clinical practitioners have noted anincrease in the occurrence of these cardiac arrhythmias uponco-administration of terfenadine with other drugs such as ketoconazoleand erythromycin or upon overdose of terfenadine. Quercia et al., Hosp.Formul. 28: 137, 142 (1993).

Leukotrienes augment neutrophil and eosinophil migration, neutrophil andmonocyte aggregation, leukocyte adhesion, increase capillarypermeability, and smooth muscle contraction, all of which contribute toinflammation, edema, mucus secretion, and bronchoconstriction. Forexample, zileuton, commercially available as ZYFLO®, is a specificinhibitor of 5-lipoxygenase and has the chemical name(±)-1-(1-Benso[b]thien-2-ylethyl)-1-hydroxyurea. Zileuton is known toinhibit leukotriene (LTH₄, LTC₄, LTD₄, and LTE₄) formation in vitro.Zileuton is an inhibitor ex vivo of LTB₄ formation in several speciesand inhibits leukotriene-dependent smooth muscle contractions in vitroin guinea pig and human airways. One study of 373 patients indicatedthat 600 mg of zileuton four times daily were required to provideefficacy, while 400 mg failed to do so. In some patients, zileuton wasreported to cause headache, pain, asthenia, dyspepsia, nausea, andmyalgia. [Physician's Desk Reference, 52 ed., Medical Economics Co.,Inc., 474-76 (1998)].

Zafirlukast, sold commercially as ACCOLATE®, is another type ofleukotriene inhibitor. This leukotriene inhibitor is a leukotrienereceptor antagonist (LTRA) of leukotriene D₄ and E₄, and has thechemical name 4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-8-ylmethmethoxy-N-o-tolylsulfonylbenzamide. Cysteinyl leukotriene production andreceptor occupation have been correlated with the pathophysiology ofasthma. In vitro studies indicated that zafirlukast antagonized thecontractile activity of three leukotrienes in conducting airway smoothmuscle from laboratory animals and humans; prevented intradermalLTD₄-induced increases in cutaneous vascular permeability; and inhibitedinhaled LTD₄-induced influx of eosinophils into animal lungs. In somepatients, zafirlukast has been reported to cause headache, infection,nausea, diarrhea, pain, asthenia, abdominal pain, dizziness, myalgia,fever, vomiting, SGPT elevation, and dyspepsia. [Physician's DeskReference, 52 ed., Medical Economics Co., Inc., 3148-49 (1998)].

SUMMARY OF THE INVENTION

The present invention represents an improvement over terfenadine and theterfenadine metabolites, as well as the leukotriene inhibitor,technology presently available.

This invention relates to novel pharmaceutical compositions comprising:(a) a metabolite of terfenadine; (b) a leukotriene inhibitor; andoptionally (c) a decongestant; and a pharmaceutically acceptable carrieror excipient. A “metabolite of terfenadine” or a “terfenadinemetabolite,” as defined herein, includes4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetates,4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl-α,α-dimethylbenzeneaceticacid (fexofenadine), and1-[p-(2-hydroxymethyl-2-propyl)phenyl)-4-[4-(α-hydroxy-α-phenylbenzyl)-1-piperidinyl]butanol,or an optically pure stereoisomer of any of the above compounds, or apharmaceutically acceptable salt of any of the above compounds orstereoisomers (See, e.g., U.S. Pat. No. 5,375,683).

The compositions of the invention employing a terfenadine metabolite anda leukotriene inhibitor, and optionally a decongestant, possess potentantihistaminic activity and are useful in treating, preventing, ormanaging asthma, asthma symptoms, allergic rhinitis, inflammation, andother allergic disorders, as well as dermatitis. The compositionsemploying a terfenadine metabolite and a leukotriene inhibitor arepreferred, and these provide an improvement in overall therapy relativeto terfenadine or a terfenadine metabolite alone. In addition, thecompositions of the invention reduce or avoid adverse effects associatedwith administration of other non-sedating antihistamines or derivativesthereof, such as terfenadine, including, but not limited to, cardiacarrhythmias, drowsiness, nausea, fatigue, weakness and headache. Thecompositions of a terfenadine metabolite and a leukotriene inhibitor arealso useful in combination with non-steroidal anti-inflammatory agentsor other non-narcotic analgesics for the treatment or prevention ofcough, cold, cold-like, and/or flu symptoms and the discomfort,headache, pain, fever, and general malaise associated therewith. Theaforementioned combinations (e.g., a terfenadine metabolite and aleukotriene inhibitor) may optionally include one or more other activecomponents including a decongestant, cough suppressant/antitussive, orexpectorant.

Additionally, the novel pharmaceutical compositions of the invention areuseful in treating, preventing, or managing motion sickness, vertigo,diabetic retinopathy, small vessel complications due to diabetes andsuch other conditions as may be related to the activity of thesederivatives as antagonists of the H-1 histamine receptor. Thecompositions can be used to treat or prevent these disorders whilereducing or avoiding adverse effects associated with administration ofother non-sedating antihistamines including α-aryl-4-substitutedpiperidinoalkanol derivatives, such as terfenadine.

In one embodiment, this invention provides for a method of preventing ortreating asthma or asthma symptoms in a human which comprisesadministering to a human a therapeutically effective amount of aterfenadine metabolite and a therapeutically effective amount of aleukotriene inhibitor.

The invention also provides a method of preventing or treating asthma orasthma symptoms in a human, comprising administering to a human acomposition, said composition comprising (i) a therapeutically effectiveamount of a terfenadine metabolite or a pharmaceutically acceptable saltthereof; (ii) a leukotriene inhibitor selected from the group consistingof 5-lipoxygenase inhibitors, 5-lipoxygenase activating proteinantagonists, and leukotriene receptor antagonists; (iii) optionally atherapeutically effective amount of a decongestant; and apharmaceutically acceptable carrier or excipient.

This invention is further directed to a method of preventing or treatingasthma or the symptoms of asthma in a human which comprisesadministering to a human therapeutically effective amounts of aterfenadine metabolite, a leukotriene inhibitor, and a decongestant.

In a second embodiment, the invention also provides for a method ofpreventing or treating allergic rhinitis in a human which comprisesadministering to a human a therapeutically effective amount of aterfenadine metabolite, or a pharmaceutically acceptable salt thereof, aleukotriene inhibitor, and optionally a decongestant, such that allthree active ingredients are used.

In a third embodiment, the invention provides for a method of preventingor treating dermatitis in a human which comprises administering to ahuman a therapeutically effective amount of a terfenadine metabolite ora pharmaceutically acceptable salt thereof, a leukotriene inhibitor, andoptionally a decongestant, such that all three active ingredients areused.

In a fourth embodiment, the invention provides for a method ofpreventing or treating inflammation in a human which comprisesadministering to a human a therapeutically effective amount of aterfenadine metabolite or a pharmaceutically acceptable salt thereof, aleukotriene inhibitor, and optionally a decongestant, such that allthree active ingredients are used.

In a fifth embodiment, the invention provides for a method of preventingor treating a condition responsive to leuktotriene inhibition in a humanwhich comprises administering to a human a therapeutically effectiveamount of a terfenadine metabolite or a pharmaceutically acceptable saltthereof, a leukotriene inhibitor, and optionally a decongestant, suchthat all three active ingredients are used.

It should be recognized that the compositions and methods include theuse of optically pure stereoisomers of the terfenadine metabolites, aswell as pharmaceutically acceptable salts of the stereoisomers. Thus,the invention includes the (R)- and (S)-enantiomer, and the racemicmixture, or a pharmaceutically acceptable salt thereof, of eachterfenadine metabolite. The methods and compositions preferably employracemic fexofenadine, or optically pure (R)-fexofenadine or(S)-fexofenadine, or pharmaceutically acceptable salts thereof, morepreferably (R)-fexofenadine substantially free of (S)-fexofenadine or(S)-fexofenadine substantially free of (R)-fexofenadine, orpharmaceutically acceptable salts thereof.

The invention encompasses the treatment, prevention, and/or managementof asthma, the symptoms of asthma, dermatitis, allergic rhinitis, orinflammation using a metabolite of terfenadine, preferably fexofenadine,and a leukotriene inhibitor. The invention also encompasses thetreatment, prevention, and/or management of these disorders with aterfenadine metabolite, a leukotriene inhibitor, and optionally adecongestant. The invention encompasses the treatment, prevention,and/or management of these disorders using a single unit dosage formthat contains a terfenadine metabolite, a leukotriene inhibitor andoptionally a decongestant, such that a terfenadine metabolite and aleukotriene inhibitor or all three active ingredients are used. However,it should be recognized that combination therapy by separateadministration of each active ingredient is also contemplated. Themethods and compositions of this invention are believed to reduce oravoid adverse effects associated with the administration of non-sedatingantihistamines, such as terfenadine. The methods and compositionsdescribed herein are believed to provide superior or improved therapyover prior art methods and compositions involving a terfenadinemetabolite in the absence of a leukotriene inhibitor, or a leukotrieneinhibitor in the absence of a terfenadine metabolite. Without beinglimited by theory, it is believed that the combination of a terfenadinemetabolite, a leukotriene inhibitor, and optionally a decongestant,provides superior, improved, and synergistic effects unachievable by anyof these compounds alone.

DETAILED DESCRIPTION OF THE INVENTION

The administration of a terfenadine metabolite, a leukotriene inhibitor,and optionally a decongestant, in the methods of the present inventionmay be either concurrently or sequentially, i.e., a terfenadinemetabolite, a leukotriene inhibitor, and the optional decongestant maybe administered as a combination (a single unit dosage) or concurrentlybut separately. They may also be provided by the sequentialadministration of a terfenadine metabolite, leukotriene inhibitor, andthe optional decongestant, by sequential administration of a terfenadinemetabolite, decongestant, and leukotriene inhibitor, by sequentialadministration of leukotriene inhibitor, a terfenadine metabolite, anddecongestant, or in any other possible order, such as decongestantfollowed by concurrent administration of a terfenadine metabolite andleukotriene inhibitor. The compositions administered in each of thesemethods may be concurrent, sequential, or in any combination ofconcurrent and/or sequential.

Adverse effects to be reduced or avoided by the methods and compositionsof the present invention include, but are not limited to:cardiotoxicity, such as cardiac arrythmia or cardiac conductiondisturbances; drowsiness; nausea; fatigue; weakness; and headache.

Terfenadine metabolites and the isomers and salts thereof, particularlyfexofenadine and the isomers and salts thereof, and other non-sedatingantihistamines have antihistaminic activity and provide therapy and areduction of symptoms for a variety of conditions and disorders relatedto allergic rhinitis and other allergic disorders, diabetes mellitus,and other conditions; however, such drugs, while offering theexpectation of efficacy, may cause adverse effects. Utilizing ametabolite of terfenadine, preferably fexofenadine, in combination witha leukotriene inhibitor, and optionally with a decongestant, results inclearer dose-related definitions of efficacy, diminished adverseeffects, a superior therapy due to synergistic activity, andaccordingly, an improved therapeutic index. It is, therefore, moredesirable to use the compositions and methods of the invention than touse terfenadine, or a metabolite thereof, or a leukotriene inhibitorseparately.

One of ordinary skill in the art is readily able to synthesizefexofenadine or the other metabolites of terfenadine, as well as theiroptically pure stereoisomers and salts thereof, used in the compositionsand methods of the invention, such as by following the teachings of U.S.Pat. Nos. 4,254,129; 5,578,610; 5,581,011; 5,589,487; and 5,663,412, thedisclosures of which are hereby expressly incorporated herein byreference thereto.

The term “adverse effects” as used herein includes, but is not limitedto, cardiac arrhythmias, cardiac conduction disturbances, appetitestimulation, weight gain, sedation, gastrointestinal distress, headache,dry mouth, constipation, and diarrhea. The term “cardiac arrhythmias”includes, but is not limited to, ventricular tachyarrhythmias, torsadesde pointes, and ventricular fibrillation.

The phrase “therapeutically effective amount” as used herein means theamount of a terfenadine metabolite that provides a therapeutic benefitin the treatment, prevention, or management of conditions that areresponsive to histamine antagonists, such as urticaria, allergicrhinitis, inflammation, symptomatic dermographism, dermatitis, asthma,allergic asthma, retinopathy or other small vessel disorders associatedwith diabetes mellitus, and the symptoms associated with asthma orallergic rhinitis such as bronchoconstriction, cough, cold, cold-like,wheezing, dyspnea, and/or flu symptoms including, but not limited to,sneezing, rhinorrhea, lacrimation, and dermal irritation.

The phrase “therapeutically effective amount” as used herein means theamount of leukotriene inhibitor that provides a therapeutic benefit inthe treatment, prevention, or management of conditions that areresponsive to leukotriene inhibitors, such as urticaria, allergicrhinitis, symptomatic dermographism, dermatitis, asthma, inflammation,retinopathy or other small vessel disorders associated with diabetesmellitus, and the symptoms associated with asthma and allergic rhinitissuch as bronchoconstriction, cough, cold, cold-like, wheezing, dyspnea,and/or flu symptoms including, but not limited to, sneezing, rhinorrhea,lacrimation, and dermal irritation.

The phrase “therapeutically effective amount” with respect todecongestant as used herein means that amount of decongestant alone, orin combination with other drugs, that provides a therapeutic benefit inthe treatment, prevention, or management of any condition that isresponsive to decongestants, such as congestion of the respiratory tractand/or the sinuses, and the symptoms associated with congestion, such ascough, cold, cold-like, wheezing, dyspnea, and/or flu symptomsincluding, but not limited to, sneezing, rhinorrhea, lacrimation, anddermal irritation.

The term “asthma” as used herein is defined as a disorder characterizedby increased responsiveness of the trachea and bronchi to variousstimuli, which results in symptoms that include, but are not limited to,wheezing, cough, shortness of breath, bronchoconstriction, dyspnea, andthe like. Asthma includes, for example, allergic asthma.

The term “dermatitis” as used herein means that disorder caused byinflammation to the skin including endogenous and contact dermatitissuch as, but not limited to: actinic dermatitis (or photodermatitis),atopic dermatitis, chemical dermatitis, cosmetic dermatitis, dermatitisaestivalis, and seborrheic dermatitis.

The term “inflammation” as used herein is a fundamental pathologicprocess of a dynamic complex of cytologic and chemical reactions thatoccur in the affected blood vessels and adjacent tissues in response toan injury or abnormal stimulation caused by a physical, chemical, orbiologic agent, including: the local reactions and resulting morphologicchanges; the destruction or removal of the injurious material; and theresponses that lead to repair and healing. The typical signs ofinflammation are redness, heat or warmth, swelling, pain, andoccasionally inhibited or lost function. All of the signs may beobserved in certain instances, although any particular sign is notnecessarily always present.

The term “leukotriene inhibitor” as used herein includes any agent orcompound that inhibits, restrains, retards or otherwise interacts withthe action or activity of leukotrienes, such as, but not limited to,5-lipoxygenase (“5-LO”) inhibitors, 5-lipoxygenase activating protein(“FLAP”) antagonists, and leukotriene receptor antagonists (“LTRAs”),including leukotriene receptor antagonists (“ILTRAs”). An exemplary LTRAis leukotriene D₄ (“LTD₄”) receptor antagonist.

The term “5-lipoxygenase inhibitor” or “5-LO inhibitor” as used hereinincludes any agent or compound that inhibits, restrains, retards orotherwise interacts with the enzymatic action of 5-lipoxygenase, suchas, but not limited to, zileuton, docebenone, piripost, and ICI-D2318.

The term “5-lipoxygenase activating protein antagonist” or “FLAPantagonist” as used herein includes any agent or compound that inhibits,restrains, retards or otherwise interacts with the action or activity of5-lipoxygenase activating protein, such as, but not limited to, MK-591and MK-886.

The term “leukotriene receptor antagonist” or “LTRA” as used hereinincludes any agent or compound that inhibits, restrains, retards orotherwise antagonizes the activity of receptors that are responsive toleukotrienes, including those responsive to leukotriene D₄. ExemplaryLTRAs include, but are not limited to, sodium1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethynyl)phenyl)-3-(2-propyl)phenyl)thio)methyl)cyclopropaneacetate;1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneaceticacid or sodium or other salts thereof, pranlukast, zafirlukast(ICI-204219), and montelukast (MK-476), the latter of which is soldcommercially as SINGULAIR®.

The magnitude of a prophylactic or therapeutic dose of a terfenadinemetabolite or leukotriene inhibitor in the acute or chronic managementof a disorder or condition will vary with the severity of the conditionto be treated and the route of administration. The dose, and perhaps thedose frequency, will also vary according to the age, body weight, andresponse of the individual patient. Suitable total daily dose ranges canbe readily determined by those skilled in the art. In general, the totaldaily dose range for a terfenadine metabolite, for the conditionsdescribed herein, is from about 0.01 mg to about 500 mg administered insingle or divided doses. For example, a preferred oral daily dose rangeshould be from about 1 mg to about 500 mg. A more preferred oral dose isabout 20 mg to about 200 mg. A preferred oral daily dose range ofdecongestant, such as pseudoephedrine, should be from about 50 mg toabout 300 mg, more preferably, about 150 mg to about 250 mg. Inaddition, suitable oral daily dosage ranges of leukotriene inhibitor canbe readily determined by those skilled in the art. For example, see thePhysician's Desk References 1998 for suitable dosages presently used forknown leukotriene inhibitors. For example, for 5-lipoxygenaseinhibitors, the oral daily dose range should be from about 20 mg to2,500 mg, preferably from about 20 mg to 800 mg. For leukotrienereceptor antagonists, the oral daily dose range should be from about 2mg to 100 mg, preferably from about 5 mg to 20 mg.

It is further recommended that children, patients aged over 65 years,and those with impaired renal or hepatic function initially receive lowdoses, and that they then be titrated based on individual responsets) orblood level(s). It may be necessary to use dosages outside these rangesin some cases as will be apparent to those skilled in the art. Further,it is noted that the clinician or treating physician will know how andwhen to adjust, interrupt, or terminate therapy in conjunction withindividual patient response.

The term “therapeutically effective amount of a terfenadine metaboliteor a pharmaceutically acceptable salt thereof” is encompassed by theabove-described dosage amounts. In addition, the terms “said compositioncomprising (i) a therapeutically effective amount of a terfenadinemetabolite or a pharmaceutically acceptable salt thereof; and (ii) atherapeutically effective amount of a leukotriene inhibitor” and “saidcomposition comprising (i) a therapeutically effective amount of aterfenadine metabolite or a pharmaceutically acceptable salt thereof;(ii) a therapeutically effective amount of a leukotriene inhibitor; and(iii) a therapeutically effective amount of a decongestant” are alsoencompassed by the above-described dosage amounts and dose frequencyschedule.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of a terfenadine metabolite andleukotriene inhibitor according to the methods of the present invention.For example, oral, intraoral, rectal, parenteral, epicutaneous,transdermal, subcutaneous, intramuscular, intranasal, sublingual,buccal, intradural, intraocular, intrarespiratory, or nasal inhalationand like forms of administration may be employed. Oral administration isgenerally preferred. For the methods to treat dermatitis, however,topical administration is preferred.

The pharmaceutical compositions used in the methods of the presentinvention, which are sterile and stable, include a terfenadinemetabolite, the metabolic derivative of terfenadine, or apharmaceutically acceptable salt thereof, a leukotriene inhibitor, andoptionally a decongestant, as the active ingredient. The compositionsmay also contain a pharmaceutically acceptable carrier or excipient, andoptionally, other therapeutic ingredients.

The term “pharmaceutically acceptable salt” refers to a salt preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids or bases or organic acids or bases. Examples of suchinorganic acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, andphosphoric. Appropriate organic acids may be selected, for example, fromaliphatic, aromatic, carboxylic and sulfonic classes of organic acids,examples of which are formic, acetic, propionic, succinic, glycolic,glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic,algenic, and galacturonic. Examples of such inorganic bases includemetallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium, and zinc. Appropriate organic bases may be selected,for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysineand procaine.

The compositions for use in the methods of the present invention caninclude suitable excipients or carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like.

Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, patches, gel caps, syrups, elixirs, gels, powders,magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs,suppositories, nasal or oral sprays, aerosols, and the like.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are employed. If desired, tablets may be coatedby standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compound foruse in the methods of the present invention may also be administered bycontrolled release means and/or delivery devices such as those describedin U.S.

Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, thedisclosures of which are expressly incorporated herein by referencethereto.

Pharmaceutical compositions for use in the methods of the presentinvention may be prepared by any of the methods of pharmacy, but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation.

For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding, in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent.

The invention is further defined by reference to the following exampledescribing in detail the preparation of the composition and thecompositions used in the methods of the present invention, as well astheir utility. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced which arewithin the scope of this invention.

EXAMPLES Example 1 A. Preparation of MethylR-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetate

4-(α-hydroxy-α-phenylbenzyl)piperidine (4.3 g) was combined with methylp-(4-chloro-1-oxobutyl)-α,α-dimethylbenzeneacetate (4.5 g), potassiumbicarbonate (2.9 g), potassium iodide (ca. 50 mg), and methyl isobutylketone (50 mL) and heated to reflux for 48 hrs. Additional4-(α-hydroxy-α-phenylbenzyl)piperidine (1.1 g) was added, and heatingwas continued for an additional 48 hrs. Upon cooling the mixture to roomtemperature, water was added and the pH of the solution was adjusted toca. 12 by addition of aqueous sodium hydroxide. The mixture wasextracted with ethyl acetate. The ethyl acetate solution was washed withsaturated aqueous sodium bicarbonate and brine and dried over sodiumsulfate. The ethyl acetate was removed on a rotary evaporator and theresidue was treated with 25% ethyl acetate in hexane. The resultingprecipitate was filtered and air dried to give methyl4-[1-oxo-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetate.This intermediate precipitate (2.4 g) was combined with tetrahydrofuran(10 mL) and (+)-β-chlorodiisopinocamphenylborane (4.5 g) and stirred for48 hrs. Methanol (10 mL) and sodium bicarbonate (1.5 g) were added tothe reaction solution, and the mixture was stirred for 12 hrs. Themixture was diluted with ethyl acetate (200 mL) and washed withsaturated aqueous sodium bicarbonate to give methylR-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetate.

B.R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneaceticacid [R-(+)-terfenadine carboxylate]

MethylR-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetate(1.2 g) was combined with potassium hydroxide (0.4 g) and ethanol (5mL), and the mixture was heated to reflux for 7 hours. The ethanol wasremoved on a rotary evaporator and the residue was dissolved in water (2mL). The aqueous solution was acidified with glacial acetic acid toprovide a solid which was recrystallized two times from 1:1methanol/ethyl acetate to giveR-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneaceticacid (R-terfenadine carboxylate) (mp=213-215° C.).

C. Preparation of MethylS-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl)-α,α-dimethylbenzeneacetate

4-(α-hydroxy-α-phenylbenzyl)piperidine (4.3 g) was combined with methylp-(4-chloro-1-oxobutyl)-α,α-dimethylbenzene-acetate (4.5 g), potassiumbicarbonate (2.9 g), potassium iodide (ca. 50 mg), and methyl isobutylketone (50 mL) and heated to reflux for 48 hours. Additional4-(ahydroxy-α-phenylbenzyl)piperidine (1.1 g) was added, and heating wascontinued for an additional 48 hours. Upon cooling the mixture to roomtemperature, water was added and the pH of the solution was adjusted toca. 12 by addition of aqueous sodium hydroxide. The mixture wasextracted with ethyl acetate. The ethyl acetate solution was washed withsaturated aqueous sodium bicarbonate and brine and dried over sodiumsulfate. The ethyl acetate was removed on a rotary evaporator and theresidue was treated with 25% ethyl acetate in hexane. The resultingprecipitate was filtered and air dried to give methyl4-[1-oxo-4-(4-hydroxydiphenyl-methyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetate.This intermediate precipitate (2.4 g) was combined with tetrahydrofuran(10 mL) and (−)-β-chlorodiisopinocamphenylborane (4.5 g) and stirred for48 hours. Methanol (10 mL) and sodium bicarbonate (1.5 g) were added tothe reaction solution and the mixture was stirred for 12 hours. Themixture was diluted with ethyl acetate (200 mL) and washed withsaturated aqueous sodium bicarbonate to give methylS-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetate.If the aforementioned intermediate precipitate was to be reacted withracemic β-chlorodiisopinocamphenylborane, then a racemic mixture ofmethyl4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetatewould be produced.

D.S-(−)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneaceticacid [S-(−)-terfenadine carboxylate]

MethylS-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetate(1.2 g) was combined with potassium hydroxide (0.4 g) and ethanol (5 mL)and the mixture was heated to reflux for 7 hours. The ethanol wasremoved on a rotary evaporator and the residue was dissolved in water (2mL). The aqueous solution was acidified with glacial acetic acid toprovide a solid which was recrystallized two times from 1:1methanol/ethyl acetate to giveS-(−)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetic acid [(S)-terfenadinecarboxylate] (mp=215-218° C.).

Various modifications of the invention in addition to those shown anddescribed herein will be apparent to those skilled in the art from theforegoing description. Such modifications are also intended to fallwithin the scope of the appended claims.

The above disclosure includes all the information deemed essential toenable those skilled in the art to practice the claimed invention.Because the cited patents or publications may provide further usefulinformation these cited materials are incorporated herein in theirentireties by reference thereto.

What is claimed is:
 1. A method for treating or preventing a conditionresponsive to leukotriene inhibition in a human which comprisesadministering to a human in need of such treatment or prevention atherapeutically effective amount of terfenadine metabolite, or apharmaceutically acceptable salt thereof, and a therapeuticallyeffective amount of a leukotriene inhibitor, or a pharmaceuticallyacceptable salt thereof.
 2. A method of treating or preventing acondition responsive to leukotriene inhibition in a human whichcomprises administering to a human in need of such treatment orprevention a composition, said composition comprising (i) atherapeutically effective amount of terfenadine metabolite, or apharmaceutically acceptable salt thereof; (ii) a therapeuticallyeffective amount of leukotriene inhibitor, or a pharmaceuticallyacceptable salt thereof, selected from the group consisting of5-lipoxygenase inhibitors, 5-lipoxygenase activating proteinantagonists, leukotriene receptor antagonists, and mixtures thereof; and(iii) a pharmaceutically acceptable carrier or excipient.
 3. The methodof claim 1 or 2 wherein the administering further comprises atherapeutically effective amount of a decongestant, or apharmaceutically acceptable salt thereof.
 4. The method of claim 1wherein the condition responsive to leukotriene inhibition comprisesasthma or a symptom thereof.
 5. The method of claim 1 wherein thecondition responsive to leukotriene inhibition comprises an allergiccondition.
 6. The method of claim 1 wherein the condition responsive toleukotriene inhibition comprises inflammation.
 7. The method of claim 1or 2, wherein the terfenadine metabolite is racemic fexofenadine, or apharmaceutically acceptable salt thereof.
 8. The method of claim 1 or 2,wherein the terfenadine metabolite is (R)-fexofenadine, or apharmaceutically acceptable salt thereof, substantially free of(S)-fexofenadine.
 9. The method of claim 1 or 2, wherein the terfenadinemetabolite is (S)-fexofenadine, or a pharmaceutically acceptable saltthereof, substantially free of (R)-fexofenadine.
 10. The method of claim4, 5, or 6 wherein the amount of terfenadine metabolite administered isfrom about 0.01 mg to about 500 mg per day.
 11. The method of claim 10wherein the amount of terfenadine metabolite administered is from about20 mg to about 200 mg per day.
 12. The method of claim 1 or 2, whereinthe leukotriene inhibitor is a 5-lipoxygenase inhibitor.
 13. The methodof claim 12 wherein the 5-lipoxygenase inhibitor is selected from thegroup consisting of zileuton, docebenone, piripost, ICI-D2318, andmixtures thereof.
 14. The method of claim 1 or 2, wherein theleukotriene inhibitor is a 5-lipoxygenase activating protein.
 15. Themethod of claim 14 wherein the 5-lipoxygenase activating protein isselected from the group consisting of MK-591, MK-886, and mixturesthereof.
 16. The method of claim 1 or 2, wherein the leukotrieneinhibitor is a leukotriene receptor antagonist.
 17. The method of claim16 wherein the 5-lipoxygenase activating protein is selected from thegroup consisting of zafirlukast, montelukast, pranlukast, sodium1(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethynyl)phenyl)-(2-hydroxy-2-propyl)phenyl)thio)methyl)cyclopropaneacetate;1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydromethylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid, and saltsand mixtures thereof.
 18. The method of claim 1 or 2, wherein thecompositions are administered as a nasal or oral spray.
 19. The methodof claim 1 or 2, wherein at least one of the terfenadine metabolite andthe leukotriene inhibitor is administered as a nasal or oral spray. 20.The method claim 1 or 2, wherein at least one of the a terfenadinemetabolite and the leukotriene inhibitor is administered in an oralsolid dosage form.
 21. The method of claim 1 or 2, wherein thetherapeutically effective amount of a terfenadine metabolite, or apharmaceutically acceptable salt thereof, and a therapeuticallyeffective amount of a leukotriene inhibitor, or a pharmaceuticallyacceptable salt thereof are administered as a nasal or oral spray. 22.The method of claim 1 or 2, which further comprises administering apharmaceutically acceptable carrier or excipient.
 23. The method ofclaim 1 or 2, wherein the amount of terfenadine metabolite orpharmaceutically acceptable salt thereof is from about 0.01 to 500 mg.24. The method of claim 1 or 2, wherein the amount of 5-lipoxygenaseinhibitor, or a pharmaceutically acceptable salt thereof is from about20 mg to 2500 mg.
 25. The method claim 1 or 2, wherein the amount of5-lipoxygenase activating protein antagonist, or a pharmaceuticallyacceptable salt thereof is from about 20 mg to 2500 mg.
 26. The methodclaim 1 or 2, wherein the amount of leukotriene receptor antagonist, ora pharmaceutically acceptable salt thereof is from about 2 mg to 200 mg.27. A pharmaceutical composition which comprises a therapeuticallyeffective amount of a terfenadine metabolite, or a pharmaceuticallyacceptable salt thereof, and a therapeutically effective amount of aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof;and a pharmaceutically acceptable carrier or excipient.
 28. Thepharmaceutical composition of claim 27 which further comprises atherapeutically effective amount of a decongestant, or apharmaceutically acceptable salt thereof.
 29. A pharmaceuticalcomposition which comprises from about 0.01 to about 500 mg of aterfenadine metabolite, or a pharmaceutically acceptable salt thereof,and from about 20 mg to about 2,500 mg of 5-lipoxygenase inhibitor, or apharmaceutically acceptable salt thereof.
 30. A pharmaceuticalcomposition which comprises from about 0.01 to about 500 mg of aterfenadine metabolite, or a pharmaceutically acceptable salt thereof,and from about 2 mg to about 200 mg of leukotriene receptor antagonist,or a pharmaceutically acceptable salt thereof.
 31. A pharmaceuticalcomposition which comprises from about 0.01 mg to about 500 mg ofterfenadine metabolite, or a pharmaceutically acceptable salt thereof,and from about 20 mg to about 2500 mg of 5-lipdcygenase activatingprotein antagonist, or a pharmaceutically acceptable salt thereof. 32.The composition of claim 27, 28, 29, 30, or 31 wherein the terfenadinemetabolite is racemic fexofenadine, or a pharmaceutically acceptablesalt thereof.
 33. The composition of claim 27, 28, 29, 30, or 31 whereinthe terfenadine metabolite comprises (S)-fexofenadine, or apharmaceutically acceptable salt thereof, substantially free of(R)-fexofenadine.
 34. The composition of claim 27, 28, 29, 30, or 31wherein the terfenadine metabolite comprises (R)-fexofenadine, or apharmaceutically acceptable salt thereof, substantially free of(S)-fexofenadine.
 35. The composition of claim 27, 28, 29, 30, or 31administered as a nasal or oral spray.
 36. The composition of claim 27,28, 29, 30, or 31 wherein at least one of the a terfenadine metaboliteand the leukotriene inhibitor is administered as a nasal or oral spray.37. The composition of claim 27, 28, 29, 30, or 31 wherein at least oneof the a terfenadine metabolite and the leukotriene inhibitor isadministered in an oral solid dosage form.